A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT

作者：Muhammad Umair Mushtaq, John F. DiPersio, Jacques Azzi, BW Cooper, Guenther Koehne, Divya Koura, Joseph E. Maakaron, John Magenau, Brian McClune, Joseph C Rimando, Nirali N Shah, Hyung Chae Suh, Kelly Beuka, John Sturrock, Mugdha Harshakumar Nikam, Eric Berglund, Jianxin Hu, Yonina Keschner, Julia Etchin, John R. Lydeard, Michele Vasquez, David O'Donnell, Guy Mundelboim, Sanjana Thosar, Giacomo Canesin, Juliana M. Xavier-Ferrucio, Sharon L. Hyzy, Deborah Lloyd, Kristin Spink, Diana Hummel, Melissa M. Lee-Sundlov, Julian Scherer, Michelle I. Lin, Jennifer Whangbo, Lori Muffly · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2025031053 · 被引用次数：5 · 研究领域：CAR-T cell therapy research、Acute Lymphoblastic Leukemia research、Hematopoietic Stem Cell Transplantation

ABSTRACT: VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts ≥5%) at dose level 1 (DL1; 1 × 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 × 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 × 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 ≥grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count...